Peptides sterically hindered

Alkyl halide, sodium hydride in DMSO 2.5.1 General, substances insoluble in common organic solvents, polysaccharides, lipopolysaccharides, peptides, sterically hindered functions, amides, amino acids Esters, and as stated for procedure 2.4 peptides containing sulfur-amino acids, histidine and arginine 132] O-Acyl groups are replaced with O-alkyl groups. For N-isopropyl amino acids, isopropyl ester formation, (see Chapter 2)... 

H Kunz, H-H Bechtolsheimer. Synthesis of sterically hindered peptides and depsipep-tides by an acid chloride method with 2-phosphonioethoxycarbonyl-(Peoc)-amino acids and hydroxy acids. Liebigs Ann Chem 2068, 1982. 

Although this methodology has been successfully used for a number of peptides, its efficacy for the cyclization of peptides with sterically hindered cyclization sites or difficult sequences of preferred extended conformation has not been investigated. 

More stable iV-acylpyridinium salts can be formed by using 4-(Ar,Ar-dialkyl-amino)pyridines. The salts are less readily hydrolyzed and are effective in the acylation of sterically hindered alcohols (72S619) and in the formation of iV-f-butoxycarbonyl derivatives of a-amino acids in aqueous alkali, for use in peptide synthesis (71CC267). 

Since the first systematic synthetic effort of Leplawy et al)22 the preparation of peptides containing the slow-reacting C -tetrasubstituted a-amino acids has been achieved mainly by solution procedures. However, recent improvements in activation methodologies make solid-phase peptide synthesis (SPPS) an attractive tool as well, at least with the less sterically hindered Ca-tetrasubstituted a-amino acids. 

This reaction has found considerable interest in peptide chemistry, since activation via an acid fluoride is mild enough to prevent raccmization of carbamate-protected amino acids." 104 On the other hand, amino acid fluorides are reactive enough for the coupling of even sterically hindered amino acids.105-109... 

Due to the suppression of racemization and the ability to couple sterically hindered substrates, this methodology has been utilized in solid-phase peptide synthesis. In particular, 9-fluorenyl-methoxycarbonyl-protected amino acid fluorides have been used with this protocol.110 1,3... 

HATU is the most powerful yet most expensive peptide coupling reagent on the market. It is preferentially used for the coupling of sterically hindered amino acids or during the synthesis of complex peptides (21) without the addition of HOBt. However, due to its high price, amino acids for which high incorporation... 

Angell, Y.M., Garcia-Echeverria, C., and Rich, D.H. (1994) Comparative studies of the coupling of N-methylated sterically hindered amino acids during solid-phase peptide synthesis. Tetrahedron Lett. 35, 5891-5894. 

Peptide microarrays are prepared by immobilizing many peptide molecules on the surface of a solid support in a small area in an addressable fashion. The immobilization can be achieved via in situ synthesis or chemical ligation through a covalent bond. A hydrophihc linker between the sohd surface and the peptide usually is added to minimize steric hinderance caused by the sohd support. The most commonly used solid support for microarray printing is a standard microscope glass slide. Other solid supports also have been used such as polystyrene, nitrocellulose membranes, PVDF membranes, Hybond ECL membranes, gold surfaces, and chemical vapor deposited diamond films. 

Similarly, carbonylimidazolinm salts have been introduced. For example, CBMIT 15 is described as an efficient amino acylating reagent for peptide synthesis with sterically hindered amino acids (36). 

Since azides are smoothly reduced on solid supports with SnCybenzenethiol/TEA (5 mmol/ 25 mmol/25 mmol for 1 mmol resin-bound azide rt, 2 this alternative procedure has been exploited for the synthesis of oligoureas on resin using a-azido acids.Similarly, azides are efficiently reduced to amines with dithiothreitol (DTT),P 1 a procedure that was successfully transferred to the reduction of a-azidoacyl peptides on resin for the SPPS with a-azido acids.In the case of sterically hindered azides, addition of small amounts of 2-sulfanylethanol to the DTT/DIPEA mixture or the use of DBU as a base enhances the reaction rates (Scheme Other reductions of azides include the use of H2S/pyridine/... 

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